The present invention relates to certain novel 3-aryl-2-hydroxypropionic acid derivatives and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.
Insulin resistance, defined as reduced sensitivity to the actions of insulin in the whole body or individual tissues such as skeletal muscle, myocardium, fat and liver, prevails in many individuals with or without diabetes mellitus. The insulin resistance syndrome, IRS, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, possibly non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, dyslipidemia observed as deranged lipoprotein levels typically characterized by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In non-insulin dependent diabetes mellitus these atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is at present only limited awareness of the need to increase the insulin sensitivity in IRS and thus to correct the dyslipidemia which is considered to cause the accelerated progress of atherosclerosis.
Furthermore there is at present no pharmacotherapy available to adequately correct the metabolic derangements associated with IRS. To date, the treatment of NIDDM has been focused on correction of the deranged control of carbohydrate metabolism associated with the disease. Stimulation of endogenous insulin secretion by means of secretagogues, like sulphonylureas, and if necessary administration of exogenous insulin are methods frequently used to normalize blood sugar but that will, if anything, further enhance insulin resistance and will not correct the other manifestations of IRS nor reduce cardiovascular morbidity and mortality. In addition such treatment involves a significant risk of hypoglycemia with associated complications.
Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as methformin, or glucosidase inhibitors, such as acarbose. Although these agents have been efficacious to a degree, their limited clinical effect is associated with side effects.
A novel therapeutic strategy involves the use of insulin sensitizing agents, such as the thiazolidinediones which at least in part mediate their effects via an agonistic action on nuclear receptors. Ciglitazone is the prototype in this class. In animal models of IRS these compounds seem to correct insulin resistance and the associated hypertriglyceridaemia and hyperinsulinemia, as well as hyperglycemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling, leading to enhanced insulin action in skeletal muscle, liver and adipose tissue.
Ciglitazone as well as later described thiazolidinediones in clinical development either have been discontinued reportedly due to unacceptable toxicity or show inadequate potency. Therefore there is a need for new and better compounds with insulin sensitizing properties.
Compounds of the Formula 
and certain derivatives thereof disclosed in U.S. Pat. No. 5,306,726 and WO 91/19702 are said to be useful as hypoglycemic and hypocholesterolemic agents, and in U.S. Pat. No. 5,232,945 said to be useful in the treatment of hypertension.
AU 650 429 discloses structurally related compounds, but claimed to have different properties: diuretic, antihypertensive, platelets anti-aggregating and anti-lipoxygenase properties.
EP 139 421 discloses compounds having the ability to lower blood lipid and blood sugar levels. Among these compounds is troglitazone, a compound that has reached the market for treatment of NIDDM or decreased glucose tolerance. WO 97/31907 discloses compounds which are claimed to show good goblood-glucose lowering activity and therefore to be of use in the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia, and are of particular use in the treatment of Type II diabetes.
These compounds are also claimed to be of use for the treatment and/or prophylaxis of other diseases including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis.
The invention relates to compounds of the general formula (I) 
and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof, in which formula
A is situated in the ortho, meta or para position and represents 
R is hydrogen;
xe2x80x94ORa, wherein Ra represents hydrogen, alkyl, aryl or alkylaryl;
xe2x80x94NRaRb, wherein Ra and Rb are the same or different and Ra is as defined above and Rb represents hydrogen, alkyl, aryl, alkylaryl, cyano, xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oaryl, xe2x80x94Oalkylaryl, xe2x80x94CORc or xe2x80x94SO2Rd, wherein Rc represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl;
R1 is alkyl, aryl, alkene, alkyne, cyano;
xe2x80x94ORe, wherein Re is alkyl, acyl, aryl or alkylaryl;
xe2x80x94Oxe2x80x94[CH2]mxe2x80x94ORf, wherein Rf represents hydrogen, alkyl, acyl, aryl or alkylaryl and m represents an integer 1-8;
xe2x80x94OCONRaRc, wherein Ra and Rc are as defined above;
xe2x80x94SRd, wherein Rd is as defined above;
xe2x80x94SO2NRaRf, wherein Rf and Ra are as defined above;
xe2x80x94SO2ORa, wherein Ra is as defined above;
xe2x80x94COORd, wherein Rd is as defined above;
R2 is hydrogen, halogen, alkyl, aryl, or alkylaryl,
R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl,
n is an integer 1-6,
D is situated in the ortho, meta or para position and represents
xe2x80x94OSO2Rd, wherein Rd is as defined above;
xe2x80x94OCONRfRa, wherein Rf and Ra are as defined above;
xe2x80x94NRcCOORd, wherein Rc and Rd are as defined above;
xe2x80x94NRcCORa, wherein Rc and Rd are as defined above;
xe2x80x94NRcCORa, wherein Rc and Ra are as defined above;
xe2x80x94NRcRd, wherein Rc and Rd are as defined above;
xe2x80x94NRcSO2Rd, wherein Rc and Rd are as defined above;
xe2x80x94NRcCONRaRk, wherein Ra, Rc and Rk are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl;
xe2x80x94NRcCSNRaRk, wherein Ra, Rc and Rk are the same or different and each represents hydrogen, alkyl, aryl or alkylaryl;
xe2x80x94SO2Rd, wherein Rd is as defined above;
xe2x80x94SORd, wherein Rd is as defined above;
xe2x80x94SRc, wherein Rc is as defined above;
xe2x80x94SO2NRaRf, wherein Rf and Ra are as defined above;
xe2x80x94SO2ORa, wherein Ra is as defined above;
xe2x80x94CN,
xe2x80x94CONRcRa, wherein Rc and Ra are as defined above;
Dxe2x80x2 is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NRfRb, wherein Rf and Rb are as defined above;
xe2x80x94ORf, wherein Rf is as defined above;
xe2x80x94OSO2Rd, wherein Rd is as defined above;
Dxe2x80x3 is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NRfRb wherein Rf and Rb are as defined above;
xe2x80x94ORf, wherein Rf is as defined above.
xe2x80x94OSO2Rd, wherein Rd is as defined above.
For ease of reference the definitions of formula I above are henceforth referred to as defined in Category A. Unless otherwise stated the definitions of the various substituents are as defined under Category A throughout the present application.
The compounds of the formula I are surprisingly effective in conditions associated with insulin resistance.
Category A2: In one embodiment the present invention does not comprise (S)-2-ethoxy-3-[4-(2-{4-[methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, and 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid.
Category A3: preferred compounds of the present invention are those of formula I, wherein A is situated in the meta or para position and represents, 
R is hydrogen;
xe2x80x94ORa, wherein Ra is as defined in Category A;
xe2x80x94NRaRb, wherein Ra and Rb are the same or different and Ra is as defined in Category A and Rb represents hydrogen, alkyl, aryl, alkylaryl, cyano, xe2x80x94OH, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is cyano;
xe2x80x94ORd, wherein Rd is as defined in Category A;
xe2x80x94Oxe2x80x94[CH2]mxe2x80x94ORa, wherein m and Ra are as defined in Category A;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94OSO2Rd, wherein Rd is as defined in Category A;
xe2x80x94OCONRaRc, wherein Ra and Rc are as defined in Category A;
xe2x80x94NRcCOORd, wherein Rc and Rd are as defined in Category A;
xe2x80x94NRcCORa, wherein Rc and Ra are as defined in Category A;
xe2x80x94NRcRd, wherein Rc and Rd are as defined in Category A;
xe2x80x94NRcSO2Rd, wherein Rc and Rd are as defined in Category A;
xe2x80x94NRcCONRkRc, wherein Ra, Rc and Rk are as defined in Category A;
xe2x80x94NRcCSNRaRk, wherein Ra, Rc and Rk are as defined in Category A;
xe2x80x94SO2Rd, wherein Rd is as defined in Category A;
xe2x80x94SRc, wherein Rc is as defined in Category A;
xe2x80x94CN;
xe2x80x94CONRaRc, wherein Ra and Rc are as defined in in Category A;
Dxe2x80x2 is situated in the ortho, meta or para position and represents hydrogen, alkyl, alkylaryl, halogen, xe2x80x94CN or xe2x80x94NO2;
xe2x80x94ORh, wherein Rh is hydrogen or alkyl;
Dxe2x80x3 is situated in the ortho, meta or para position and represents hydrogen, alkyl, alkylaryl, halogen, xe2x80x94CN or xe2x80x94NO2;
xe2x80x94ORh, wherein Rh is as defined above.
Category A4: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position;
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3,
D is situated in the ortho, meta or para position and represents
xe2x80x94NRcCOORd, wherein Rc, and Rd are as defined in Category A;
Dxe2x80x2 is hydrogen.
Dxe2x80x3 is hydrogen.
Category A5: further preferred compounds of the present invention are those within Category A4, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents xe2x80x94NRhCOORd, wherein
Rd is as defined in Category A and Rh represents hydrogen or alkyl.
Category A6: further preferred compounds of the present invention are those within Category AS, wherein
D is xe2x80x94NRjCOOalkyl wherein Rj represents hydrogen and lower alkyl.
Category A7: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position.
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94NRcCORa, wherein Rc and Ra are as defined in Category A;
Dxe2x80x2 is hydrogen.
Dxe2x80x3 is hydrogen.
Category A8: further preferred compounds of the present invention are those within Category A7 wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents xe2x80x94NRhCORd, wherein
Rd is as defined in Category A and Rh represents hydrogen or alkyl.
Category A9: further preferred compounds of the present invention are those within Category A8, wherein
D is xe2x80x94NHCORd, wherein Rd is as defined in Category A.
Category A10: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position,
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl,
R2 is hydrogen;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94SO2Rd, wherein Rd is as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A11: further preferred compounds of the present invention are those within Category A10, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position and represents xe2x80x94SO2Rd, wherein Rd is as defined in Category A.
Category A12: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position,
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen;
R3 is hydrogen or alkyl,
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94SRd, wherein Rd is as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A13: further preferred compounds of the present invention are those within Category A12, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position and represents xe2x80x94SRd, wherein Rd is as defined in Category A.
Category A14: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position,
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl, alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3,
D is situated in the ortho, meta or para position and represents
xe2x80x94OCONRaRc, wherein Ra and Rc are as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A15: further preferred compounds of the present invention are those within Category A14, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl, xe2x80x94NHCN;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents
xe2x80x94OCONHRd, wherein Rd is as defined in Category A.
Category A16: further preferred compounds of the present invention are those within Category A15, wherein
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
D is xe2x80x94OCONHalkyl.
Category A17: further preferred compounds of the present invention are those within
Category A3, wherein
A is situated in the meta or para position,
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl, alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl,
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl,
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94NRcSO2Rd, wherein Rc and Rd are as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A18: further preferred compounds of the present invention are those within Category A17, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents
xe2x80x94NRhSO2Rd, wherein Rd is as defined in Category A and Rh is hydrogen or alkyl.
Category A19: further preferred compounds of the present invention are those within Category A18, wherein
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
D is xe2x80x94NRhSO2alkyl wherein Rh is as defined above.
Category A20: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position;
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94NRcRd, wherein Rc and Rd are as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A21: further preferred compounds of the present invention are those within Category A20, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents
xe2x80x94NRhRd wherein Rd is as defined in Category A and Rh is hydrogen or alkyl.
Category A22: further preferred compounds of the present invention are those within Category A21, wherein
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
D is xe2x80x94NRhalkyl wherein Rh is hydrogen or alkyl.
Category A23: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position;
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl,
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94NRcCONRaRk, wherein Ra, Rc and Rk are as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A24: further preferred compounds of the present invention are those within Category A23, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents
xe2x80x94NHCONHRd, wherein Rd is as defined in Category A.
Category A25: further preferred compounds of the present invention are those within Category A24, wherein
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
D is xe2x80x94NHCONHalkyl.
Category A26: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position;
R is xe2x80x94ORa, wherein Ra is hydrogen, alkyl or alkylaryl;
NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94NRcCSNRaRk, wherein Ra, Rc and Rk are as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A27: further preferred compounds of the present invention are those within Category A26, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R2 is hydrogen;
R3 is hydrogen;
n is the integer 1;
D is situated in the para position, and represents xe2x80x94NHCSNHRd, wherein Rd is as defined in Category A.
Category A28: further preferred compounds of the present invention are those within Category A27, wherein
R1 is xe2x80x94Olower alkyl.
D is xe2x80x94NHCSNHalkyl.
Category A29: further preferred compounds of the present invention are those within Category A3, wherein
A is situated in the meta or para position;
R is xe2x80x94ORa, wherein Ra is hydrogen, alky, alkylaryl;
xe2x80x94NHRb, wherein Rb is hydrogen, alkyl, alkylaryl, cyano, xe2x80x94Oalkyl or xe2x80x94Oalkylaryl;
R1 is xe2x80x94Oalkyl;
R2 is hydrogen or alkyl;
R3 is hydrogen or alkyl;
R4 is hydrogen;
n is an integer 1-3;
D is situated in the ortho, meta or para position and represents
xe2x80x94OSO2Rd, wherein Rd is as defined in Category A;
Dxe2x80x2 is hydrogen;
Dxe2x80x3 is hydrogen.
Category A30: further prefered compounds of the present invention are those within Category A29, wherein
A is situated in the para position;
R is xe2x80x94OH, xe2x80x94Oalkyl, xe2x80x94Oalkylaryl;
xe2x80x94NH2, xe2x80x94NHOalkylaryl or xe2x80x94NHCN;
R2 is hydrogen;
R3 hydrogen;
n is the integer 1;
D is situated in the para position and represents
xe2x80x94OSO2alkyl or xe2x80x94OSO2alkylaryl.
Category A31: further preferred compounds of the present invention are those within Category A30, wherein
R1 is xe2x80x94Oalkyl, preferably xe2x80x94Olower alkyl;
D is xe2x80x94OSO2 alkyl.
Category A32: further preferred compounds of the invention are
2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid;
3-{4-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid;
2-Ethoxy-3-{4-[2-(4-methanesulfonylphenyl)ethoxy]phenyl}propanoic acid;
2-Ethoxy-3-{4-[2-(4-methylsulfanylphenyl)ethoxy]phenyl}propanoic acid;
2-Ethoxy-3-[4-(2-{4-isobutyrylaminophenyl}ethoxy)phenyl]propanoic acid;
3-{4-[2-(4-tert-Butylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester;
2-Ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid;
N-Cyano-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide;
N-Benzyloxy-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide;
2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide;
2-Ethoxy-3-{4-[3-(3-methanesulfonyloxyphenyl)propoxy]phenyl}propanoic acid ethyl ester;
2-Ethoxy-3-(4-{2-[4-(2-propanesulfonyloxy)phenyl]ethoxy}phenyl)propanoic acid;
3-[4-{2-(4-[tert-Butoxycarbonyl(methyl)amino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid;
(S)-2-Ethoxy-3-[4-{2-[4-(methoxycarbonylamino)phenyl)ethoxy]phenyl}propanoic acid;
2-Ethoxy-3-{4-[2-(4-methylcarbamoyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester;
3-[4-{2-(4-[Benzyloxycarbonylamino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid;
3-{4-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]-3-methoxyphenyl}-2-ethoxypropanoic acid;
3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid methyl ester;
(S)-2-Ethoxy-3-(4-{2-[4-(phenylsulfonyl)phenyl]ethoxy}phenyl)propanoic acid;
and, where applicable, stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof.
Category A33: further preferred compounds of the present invention are compounds which are one of the possible enantiomers.
When alkyl is included in the substituent D the preferred alkyls are methyl, ethyl, propyl, isopropyl and tertiary butyl.
When the substituent R1 represents an alkyl group, the preferred alkyls are alkyl groups having from 2 to 6 carbon atoms.
When the substituent ORa represents an alkylaryl group, the preferred alkylaryl is benzyl.
In the present specification the expression xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d is intended to define but is not limited to such base salts as the alkali metal salts, alkaline earth metal salts, aluminium, zinc and bismuth salts, ammonium salts, salts with basic amino acids, and salts with organic amines.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof (with the exception of the compounds of Category A2), as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates. Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization. The enantiomers may be isolated by separation of racemate for example by fractional crystallization, resolution or HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallization, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention.
The following definitions shall apply throughout the specification and the appended claims.
Unless otherwise stated or indicated, the term xe2x80x9calkylxe2x80x9d denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl having from 3 to 6 carbon atoms. The term xe2x80x9clower alkylxe2x80x9d denotes a straight or branched, substituted or unsubstituted alkyl group having from 1 to 3 carbon atoms or a cyclic alkyl having 3 carbon atoms. Examples of said alkyl and lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl as well as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Unless otherwise stated or indicated, the term xe2x80x9calkoxyxe2x80x9d denotes a group O-alkyl, wherein alkyl is as defined above.
Unless otherwise stated or indicated, the term xe2x80x9chalogenxe2x80x9d shall mean fluorine, chlorine, bromine or iodine.
Unless otherwise stated or indicated, the term xe2x80x9carylxe2x80x9d denotes a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl group, or a fused ring system of any of these groups, such as naphthyl.
Unless otherwise stated or indicated, the term xe2x80x9csubstitutedxe2x80x9d denotes an alkyl or an aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, aryl or cyano groups.
Unless otherwise stated or indicated, the term xe2x80x9calkylarylxe2x80x9d denotes a 
wherein n is an integer 1 to 6 and Rr and R1 are the same or different and each represents hydrogen or an alkyl or aryl group as defined above.
Unless otherwise stated or indicated, the term xe2x80x9cacylxe2x80x9d denotes a group 
wherein Rj is hydrogen, alkyl, alkoxy, aryl and alkylaryl as defined above.
Unless otherwise stated or indicated, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d denote a straight or branched, substituted or unsubstituted unsaturated hydrocarbon group having one or more double or triple bonds and having a maximum of 6 carbon atoms, preferably 3 carbon atoms.
Unless otherwise stated or indicated the term xe2x80x9cprotective groupxe2x80x9d (Rp) denotes a protecting group as described in the standard text xe2x80x9cProtecting groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. The protective group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin.
The compounds of the invention may be prepared as outlined below according to any of methods A-J. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the prior art.
A. The compounds of the invention of formula I wherein R2 and R4 are hydrogen can be prepared by a condensation reaction, such as a Knoevenagel or Wittig type reaction, of a carbonyl compound of the formula II 
xe2x80x83with a compound of the formula III or IV 
xe2x80x83in which formulas D, Dxe2x80x2, Dxe2x80x3, n, R, R1 and R3 are as defined in Category A and L1=L2=L3 are phenyl or L1=L2 are ORd (wherein Rd is as defined in Category A) and L3 is xe2x95x90O, and if desired, followed by reduction of the obtained double bond and removal of protective groups.
A1. In the condensation step approximately equimolar amounts of reactants are mixed in the presence of a base, such as sodium acetate, piperidine acetate, LDA or potassium tert-butoxide to provide the compound of formula I wherein A is the unsaturated moiety. This step may be carried out in the presence of an inert solvent or in the absence of solvent in which case the temperature should be sufficiently high to cause at least partial melting of the reaction mixture, a preferred such temperature is in the range of 100xc2x0 C. to 250xc2x0 C.
Sometimes it is necessary to add a dehydrating agent such as p-toluenesulfonic acid in order to achieve the formation of the double bond.
In a typical such reaction the aldehyde or ketone starting material and the compound of formula III are combined in approximately equimolar amounts and molar excess, preferably 1-5 fold, of anhydrous sodium acetate and the mixture is heated until it melts if necessary under vacuum. The compound of formula I wherein A is the unsaturated moiety, can then be isolated by mixing with water and acetone, followed by filtration of the formed precipitate. The crude product can be purified if desired, e.g. by recrystallization or by standard chromatographic methods.
This reaction can also be performed conveniently in a solvent such as toluene in the presence of piperidine acetate. The reaction mixture is refluxed in a Dean-Stark apparatus to remove water. The solution is then cooled and the olefin product isolated and purified, by standard methods.
The reaction can also be performed by mixing the aldehyde or ketone and the compound of formula II in dry tetrahydrofuran, slowly adding potassium tert-butoxide at xe2x88x9220xc2x0 C. and quenching the reaction with acetic acid. The crude product is isolated and then dissolved in toluene and refluxed with p-toluenesulfonic acid in an Dean-Stark apparatus to remove the water. The product is then isolated and purified, by standard methods.
A2. The reaction can also be performed in the presence of titanium (IV) chloride and pyridine in an inert solvent, such as chloroform.
A3. The condensation step could also be performed as a Wittig-type reaction (cf. Comprehensive Organic Synthesis vol. 1 p. 755-781 Pergamon Press) or as described in the experimental part.
Approximately equimolar amounts of reactants II and IV, are mixed in the presence of a base such as tetramethylguanidine or potassium carbonate in a 1-5-fold molar excess. This reaction may be carried out in the presence of an inert solvent such as dichloromethane or isopropanol at a suitable temperature (xe2x88x9210xc2x0 C.-+60xc2x0 C.) and at a time long enough.
The compound of the formula II is prepared by coupling a compound of the formula V 
with a compound of the formula VI 
in which formulas D, Dxe2x80x2, Dxe2x80x3, n and R3 are as defined in Category A, at, for example alkylation conditions or by a Mitsunobu reaction (Tsunoda, Tetr. Lett. 34, 163942 (1993), when necessary followed by modifications of the D-groups as described in the experimental section.
The group R1 can be xe2x80x94OH or a leaving group, such as halogen, sulfonate or triflate.
The alkylation reaction and the Mitsunobu reaction can be carried out as described below or as in the experimental section.
The compounds of formula III, IV, V or VI are either commercially available or can be prepared by standard procedures known to anyone skilled in the art from commercially available starting materials or by procedures described in the experimental section. The reduction of the olefin may be carried out by using a wide variety of reducing methods known to reduce carbon-carbon double bonds, such as catalytic hydrogenation in the presence of an appropriate catalyst, magnesium or sodium amalgam in a lower alcohol such as methanol, or hydrogen transfer reagents such as diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
The catalytic hydrogenation can be conducted in alcohol, cellosolves, protic polar organic solvents, ethers, lower alifatic acids, and particularly in methanol, ethanol, methoxyethanol, dimethylformamide, tetrahydrofuran, dioxane, dimetoxyethane, ethyl acetate or acetic acid, either used alone or in mixture. Examples of the catalyst used include palladium black, palladium on activated charcoal, platinum oxide or Wilkinson""s catalyst. The reaction can proceed at different temperatures and pressures depending on the reactivity of the aimed reaction.
In case of hydrogen transfer reaction with diethyl-2,5-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, equimolar amounts of reactants are mixed and the mixture is warmed to melting (140xc2x0 C.-250xc2x0 C.) under inert atmosphere or under vacuum.
B. The compounds of the invention of formula I where A=xe2x80x94CR3R4xe2x80x94CR1R2xe2x80x94COR, wherein R4 is hydrogen can be prepared by reacting a carbonyl compound of formula II 
xe2x80x83with a compound of formula VII 
xe2x80x83in which formulas D, Dxe2x80x2, Dxe2x80x3, n, R1 and R3 are as defined in Category A and R2 is alkyl, aryl or alkylaryl, followed by dehydroxylation and if necessary by removal of protective groups.
In the reaction the compound of formula II is reacted with a compound of formula VII in the presence of a strong base such as LDA in an inert solvent followed by addition of a dehydroxylating agent such as borontrifluoride etherate.
The reaction can be carried out as described in the experimental section or by standard methods know to anyone skilled in the art.
The compound of formula VII are either commercially available or can be prepared by standard procedures.
C. The compounds of the invention of formula I where A=CR3R4xe2x80x94CR1R2xe2x80x94COR, can be prepared by an alkylation reaction with a compound of formula VIII 
xe2x80x83where in X is a leaving group, such as halogen, sulfonates or triflates, on a compound of formula VII, 
xe2x80x83in which formulas D, Dxe2x80x2, Dxe2x80x3, n, R, R1, R2, R3 and R4 are as defined in Category A and, if desired, followed by removal of protective groups.
In the alkylation step the compound of formula VII is reacted with a compound of formula VIII in the presence of one or more bases such as potassium carbonate, triethylbenzylammonium chloride, sodium hydride, LDA, butyllithium or LHMDS and in a inert solvent such as acetonitrile, DMF or dichloromethane at a suitable temperature and time. The reaction can be carried out as described in the examples or by standard methods known in the literature. (Synth. Comm. 19(788)1167-1175 (1989)).
The compound of formula VIII can be prepared from an alcohol of formula IX 
wherein D, Dxe2x80x2, Dxe2x80x3, n, R3 and R4 are as defined in Category A using standard methods or as described in the experimental section.
The compound of formula IX can be prepared from a compound of formula II either by reduction with a reducing agent known to convert a carbonyl group to a hydroxyl group such as lithium borohydride or sodium borohydride or by reaction with an organometallic compound such as an organolithium or a Grignard reagent by standard methods or as described in the experimental section.
D. The compounds of the invention of formula I can be prepared by reaction of a compound of the formula 
xe2x80x83with a compound of the formula X 
xe2x80x83in which formulas D, Dxe2x80x2, Dxe2x80x3, n and A are as defined in Category A, and R1 is xe2x80x94OH or a leaving group such as halogen, sulfonate, triflate, either by an alkylation reaction or a Mitsunobu reaction, when nessecary followed by removal of protective groups.
The compound of formula X can be prepared in accordance to method A from commercially available starting materials and compounds of formula III or IV.
D1. In an alkylation reaction the leaving group R1 can be a sulfonate such as mesylate, nosylate, tosylate, or a halogen, such as bromine or iodine. The compounds of formula V and X, in approximately equimolar amounts or with an excess of one of the compounds, are heated to reflux temperature in an inert solvent, such as isopropanol or acetonitrile, in the presence of a base, such as potassium carbonate or cesium carbonate.
The mixture is refluxed for the necessary time, typically between 0.5 h to 24 h, the work up procedure usually include filtration, for removal of solid salt, evaporation and extraction with water and an organic solvent such as dichloromethane, ethyl acetate, or diethyl ether. The crude product is purified if desired e.g. by recrystallization or by standard chromatographic methods.
D2. The Mitsunobu reaction can be carried out according to standard methods.
In a typical Mitsunobu reaction a compound of formula V, wherein the group R1 is a hydroxyl group, and a compound of formula X are mixed, in approximately equimolar amounts or with an excess of one of the compounds, in an inert solvent, such as chloroform, dichloromethane, or tetrahydrofuran. A slight molar excess of an azodicarboxylate, (1-4 equivalents) such as DEAD or ADDP and a phosphine (1-4 equivalents), such as tributylphosphine or triphenylphosphine are added and the reaction mixture is stirred at a temperature high enough, for example room temperature, and a time long enough (1-24 hours) to obtain the crude product, which can be worked up according to standard litterature methods and if desired purified, e.g. by standard chromatographic methods.
E. The compounds of the invention of formula I, wherein A is xe2x80x94CR3R4xe2x80x94CR1RR2xe2x80x94COR, wherein R, R2, R3 and R4 are as defined in Category A and R1 is xe2x80x94ORe, wherein Re is as defined in Category A, xe2x80x94Oxe2x80x94[CH2]mxe2x80x94ORf, wherein m and Rf are as defined in Category A, xe2x80x94OCONRaRc, wherein Ra and Rc are as defined in Category A, can be prepared by converting a compound of formula XI 
xe2x80x83wherein D, Dxe2x80x2, Dxe2x80x3, n, R, R2, R3 and R4 are as defined in Category A and Xxe2x80x3 is xe2x80x94OH followed, if necessary, by removal of protective groups.
The reaction may be carried out as an alkylating reaction, a Mitsunobu reaction, an esterfication reaction or by reaction with isocyanates. The alkylating reaction may be carried out using a variety of alkylating agents, such as alkyl halide. The esterfication reaction may be carried out using a variety of acylating agents such as Clxe2x80x94COxe2x80x94Rd (wherein Rd is as defined in Category A) and the Mitsunobu reaction may be carried out using an alcohol such as phenol. The reactions can be carried out in accordance with methods known to those skilled in the art or as described in the examples.
The compound of formula XI can be prepared by reaction of a compound of formula V 
with a compound of formula XII 
wherein D, Dxe2x80x2, Dxe2x80x3, n, R, R2, R3, R4 are as defined in Category A and R1 is xe2x80x94OH or a leaving group such as halogen, sulfonate or triflate and Xxe2x80x3 is xe2x80x94OH followed, if necessary, by removal of protective groups.
The reaction can be performed as described above or by standard methods know to anyone skilled in the art.
The compound of the formula XII can be prepared according to literature methods from commercially available starting materials.
F. The compounds of the formula I wherein A is xe2x80x94CR3R4xe2x80x94CR1R2xe2x80x94COR, and R, R2, R3 and R4 are as defined in Category A and R1 is xe2x80x94SRd, wherein Rd is as defined in Category A, can be prepared by reacting a compound of the formula XIII 
xe2x80x83wherein D, Dxe2x80x2, Dxe2x80x3, n, R, R2, R3, R4 are as defined in Category A and Xxe2x80x2 is halogen, a thiol in a substitution reaction. The reaction can be carried out in accordance to methods known to those skilled in the art or as described in the examples.
The compound of formula XIII can be prepared in accordance to method D from either commercially available starting materials or from starting materials prepared by standard procedures from commercially available starting materials.
G. The compounds of the invention of formula I wherein D is xe2x80x94OSO2Rd, xe2x80x94SRc, xe2x80x94OCONRfRa, xe2x80x94NRcCOORd, xe2x80x94NRcCORa, xe2x80x94NRcRd, xe2x80x94NRcCONRaRk, NRcSO2Rd and xe2x80x94NRcCSNRaRk, wherein Ra, Rc, Rd, Rf, Rg and Rk are as defined in Category A, can be prepared by reacting a compound of formula XIV 
xe2x80x83wherein Dxe2x80x2, Dxe2x80x3, n and A are as defined in Category A and X1=xe2x80x94OH, xe2x80x94SH or xe2x80x94NRcH, with a suitable reagent, such as a sulfonylhalide, isocyanate, acylhalide, chloroformate, anhydride or an alkylhalide in an inert solvent such as dichloromethane or toluene and when necessary in the presence of a base, such as triethylamine or pyridine and eventually followed by removal of protective groups.
The reaction can be carried out in accordance with methods know to those skilled in the art or as described in the examples.
H. The compounds of the invention of formula I where R is xe2x80x94OH can be prepared from a compound of formula I where in R is xe2x80x94ORp, wherein Rp is a protective group such as alkyl, aryl, alkylaryl or a polymer resin such as Wang resin or 2-chlorotrityl chloride resin, by removal of the protective group by hydrolysis. The hydrolysis can be performed according to standard methods either under basic or acidic conditions.
I. The compound of the invention of formula I wherein R is xe2x80x94NRaRb can be prepared by reacting a compound of formula I when R is xe2x80x94OH with a compound of formula HNRaRb in the presence of a peptide coupling system (e.g. EDC, DCC, HBTU, TBTU or PyBop or oxalylchloride in DMF), an appropriate base (e.g. pyridine, DMAP, TEA or DiPEA) and a suitable organic solvent (e.g. dichloromethane, acetonitrile or DMF) in accordance to methods known to those skilled in the art or as described in the examples.
J. The compounds of the invention of formula I where D is xe2x80x94SO2Rd or xe2x80x94SOR , wherein Rd is as defined in Category A, can be prepared by oxidizing a compound of formula XV 
xe2x80x83wherein Dxe2x80x2, Dxe2x80x3, n and A are as defined in Category A and X2 is xe2x80x94SORd or xe2x80x94SRd, wherein Rd is as defined in Category A with oxidizing agents such as m-chloroperoxybenzoic acid or hydrogen peroxide in an inert solvent such as dichloromethane eventually followed by removal of protective groups.
The reactions can be carried out according to standard procedures or as described in the experimental section.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
In any of the preceeding methods of preparation A-J, where necessary, hydroxy, amino or other reactive groups may be protected using a protecting group, Rp as described in the standard text xe2x80x9cProtective groups in Organic Synthesisxe2x80x9d, 2nd Edition (1991) by Greene and Wuts. The protecting group Rp may also be a resin, such as Wang resin or 2-chlorotrityl chloride resin. The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore. Protecting groups may be removed in accordance to techniques which are well known to those skilled in the art.
The expression xe2x80x9cinert solventxe2x80x9d refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as a free acid, or a pharmaceutical acceptable organic or inorganic base addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
The compounds of the invention may also be combined with other therapeutic agents which are useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidemias, dyslipidemias, diabetes and obesity.
Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.0001-100 mg/kg body weight, preferably 0.001-10 mg/kg body weight.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
The present compounds of formula (I) will be adapted for the prophylaxis and/or treatment of clinical conditions associated with reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders. These clinical conditions will include, but will not be limited to, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, non insulin dependent diabetes mellitus (NIDDM) and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic lipoprotein profile of phenotype B, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoproteins (VLDL) triglycerides, low high density lipoproteins (HDL) cholesterol and the presence of small, dense, low density lipoproteins (LDL). Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis. These cardiovascular disease conditions include macro-angiophaties causing myocardial infarction, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect compounds of formula (1) are also expected to reduce the progress of clinical conditions associated with chronic hyperglycaemia in diabetes like the micro-angiophaties causing renal disease and retinal damage. Furthermore the compounds may be useful in treatment of various conditions outside the cardiovascular system associated with insulin resistance like the polycystic ovarian syndrome.